Monoclonal antibody therapy has provided an opportunity to target and destroy tumors using antibodies engineered against tumor-specific antigens. In general, monoclonal antibody therapy stimulates a patient's immune system to attack malignant tumor cells or prevents tumor growth by blocking or inhibiting specific cell receptors. Treatment requires identification of a tumor-specific antigen on a cell-surface molecule. Representative cell-surface molecules targeted in clinical trials include those originating from various lymphomas/leukemias (such as T-cell and/or B-cell lymphomas/leukemias) and solid tumors (such as epithelial tumors of the breast, colon, and lung). Promising results have been reported in the treatment of metastatic colorectal cancer and head and neck cancer with humanized monoclonal antibodies, particularly treatments targeting epidermal growth factor receptor (EGFR, EGF receptor), a signaling protein that normally controls cell division.
EGFR (also known as ErbB-1 and HER1 in humans) is the cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands (Herbst, 2004, Int. J. Radiat. Oncol. Biol. Phys. 59 (2 Suppl):21-6). The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related proteins: EGFR (ErbB-1), HER2/neu (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4). Mutations affecting EGFR expression or activity can result in cancer. In point of fact, EGF receptors are overexpressed in most epithelial malignancies including those of the colon and the rectum. The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle.
The development of a monoclonal antibody therapy based on the discovery of the role of EGF receptors in the etiology of certain cancers first involved the development of a murine-based antibody. Immunization of mice with human A431 epidermoid carcinoma cells expressing high levels of EGFR resulted in antibodies that bound specifically to the extracellular portion of EGFR (El-Gewely, 2006, Biotechnology Annual Review (Amsterdam, Elsevier) at page 177). The monoclonal antibody, known as MAb225, bound specifically to the human EGFR with an affinity equal to its ligand, competed with ligand binding, and blocked the activation of the receptor tyrosine kinase (Goldstein et al., 1995, Clin. Cancer Res. 1:1311-1318).
Murine antibodies have the potential to generate an unwanted immunogenic response in patients. Murine antibody 225 was therefore chimerized with human IgG1 to produce a recombinant, human/mouse chimeric monoclonal antibody known as C225 having constant regions of human IgG1κ origin and variable murine regions that bind specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). C225 is believed to work mainly by blocking the EGF binding to EGFR, thereby “starving” the tumor of needed growth factor. C225 also binds specifically to EGFR on normal cells, and competitively inhibits the binding of EGF and other ligands, such as transforming growth factor—alpha. Binding results in the blocking of phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor (VEGF) production.
C225 is commercially known as Erbitux® (cetuximab) and is marketed by ImClone and Bristol-Myers Squibb in the United States, and elsewhere by Merck KgaA. Erbitux® was approved by the FDA in March 2006 for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapy. Erbitux® is also indicated for treatment of metastatic colon cancer in combination with irinotecan (Camptosar®), a DNA topoisomerase blocker.
Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status has recently been shown to be predictive of response to cetuximab therapy in colorectal cancer (Van Cutsem et al., 2008, J. Clin. Oncol 26 (May 20 suppl): Abstract 2). KRAS is a GTPase with a role in a number of signal transduction pathways. Mutations in the gene which encodes KRAS, present in over 25% of colorectal cancers, is predictive of the success of EGFR-inhibiting drugs. Expression of the mutated KRAS gene results in a diminished response to EGFR-inhibitor therapy. KRAS mutations can be detected by commercially available laboratory diagnostics.
Erbitux® elicits an immune response in about 5% of patients. Such an immune response can result in an immune complex-mediated clearance of the antibodies or fragments from the circulation, and make repeated administration unsuitable for therapy, thereby reducing the therapeutic benefit to the patient and limiting the re-administration of the antibody. Further, Erbitux® antibody causes an acneform rash in 90% of patients, with debilitating rashes found in as many as 10% of drug recipients. Other significant side effects include mucosal surface problems, malaise, nausea, fever, gastrointestinal problems, and headache (Chabner et al., 2008, Harrison's Manual of Oncology (New York: McGraw-Hill Medical), at pages 117-118). Finally, additional problems associated with the use of tumor-specific or tumor-selective monoclonal antibodies such as Erbitux® as therapeutic agents include antigenic variation of the tumor, inefficient killing of cells after binding the monoclonal antibody, inefficient penetration of the antibody into the tumor mass, and soluble target antigens mopping up the antibody.
Accordingly, there is a need to provide improved monoclonal antibodies which interfere with EGFR receptor signaling that overcome one or more of these problems, for example, by generating variants with higher affinity than Erbitux® that can be administered at reduced dosages (and thus whose administration results in reduced immunogenicity as compared to Erbitux®), or variants with reduced immunogenicity and other side-effects as compared to Erbitux®.
Citation or identification of any reference in Section 3 or in any other section of this application shall not be construed as an admission that such reference is available as prior art to the present disclosure.